Because the precise etiology of many malignant and non-malignant diseases remains unknown, no cure for these diseases exists and effective agents are not always conventionally available for treatment of a specific disease. Such diseases have been treated, for example, by surgical techniques or by non-surgical methods including chemotherapy, radiation and therapeutics. Any value of such methods, however, is often diminished by adverse side effects or risks attendant with their use.
Therapeutics used in the treatment of such diseases fall into two classes. The first class of therapeutics, symptomatics, act on the symptoms of the disease, exerting effects both upon and throughout the total course of administration. Such symptomatics include salicylic acid, glucocorticoids and non-steroidal anti-inflammatory agents, such as inodomethacin. The second class of therapeutics act on the pathogensis of the disease, exerting their effects only after the initial weeks of administration, yet having effects lasting beyond the cessation of treatment. Such therapeutics include cortisones and immunosuppressants.
These prior therapeutic agents typically must be administered over long periods of time and are often characterized by adverse side effects. For example, those that are immunosuppressants may increase the patient's susceptibility to infection.
Interferons such as alpha interferon, beta interferon, and gamma interferon have been used as therapeutic agents in varying dosages and via several modes of administration. Generally, daily or weekly dosages of more than 20-50 million International units ("I.U.") of interferon are considered to be high, while dosages up to about 10 million I.U. are considered to be low. During the initial phase of therapeutic use, these interferons were available in small quantities which permitted the administration of dosages of less than 3 million I.U. With the development of recombinant DNA technology, however, large amounts of interferons could be produced by cloning and expression in various host/vector systems. The availability of such increased amounts of interferons led to the use of high dosages in the treatment of diseases. Since that time, dosages of less than 3 million I.U. have, as a rule, only been used in tolerance and toxicity tests or in pharmokinetic studies.
Low dose regimens of up to about 3 million I.U. of alpha or beta interferons have been reported to be ineffective for the systemic treatment of tumors and virus diseases or inferior to higher doses in those treatments. See, for example, J. M. Kirkwood and M. S. Ernstoff, "Interferons In The Treatment Of Human Cancer", J. Clin. Oncol., 2, pp. 336-52 (1984); A. Billiau, Contr. Oncol., 20, pp. 251-69 (1984); E. M. Bonnem and R. J. Spiegel, Interferon-.alpha.: Current Status And Future Promise", J. Biol Resp. Modif., 3, pp. 580-98 (1984); T. C. Merigan et al., "Human Leukocyte Interferon For The Treatment Of Herpes Zoster In Patients Wich Cancer", N. Engl. J. Med., 298, pp. 981-87 (1978); E. Heidemann et al., "Fibroblasten-Interferon zur Behandlung des Herpes Zoster" ("Fibroblast-Interferon In The Treatment Of Herpes Zoster: A Pilot Study"), Dtsch. Med. Wschr., 107, pp. 695-97 (1982); S. Levin, "Clinical Use Of Interferon In Viral Infections", Isr. J. Med. Sci., 19, pp. 955-58 (1983); R. L. Knobler et al., Neurology, 34, pp. 1273-79 (1984); M. A. Faerkkilae et al., Act. Neur. Sci., 69, pp. 184-85 (1985), S. B. Greenberg and M. W. Harmon, J. A. Armstrong in P. E. Came and W. A. Carter: Interferons and Their Applications, Springer Verlag (1984). Only upon local treatment (intratumoral, peritumoral, intraventricular, intrathecal, intralesional, perilesional or intranasal application) have doses of less than 3 million I.U. been reported to demonstrate activity comparable to that effected by systemic application of higher doses.
In the case of the acute viral disease herpes zoster, a dose of 0.5 million I.U. alpha interferon or beta interferon per kilogram of body weight per day was reported to be acceptable, i.e. in the case of adults, about 30 million I.U. a day [T. C. Merigan, supra; E. Heidemann et al., Onkologie, 7, pp. 210-12 (1984)]. In the treatment of chronic viral diseases, such as chronically active hepatitis B infections, 3 to 10 million I.U. of alpha interferon or beta interferon are typically administered daily or three times a week. [R. Muller et al., Z. Gastroenterologie, 20, pp. 105-109 (1982); A. Billiau, supra, S. Levin, supra.] Daily doses of 6 or 200 million I.U. of alpha interferon have been administered to patients afflicted with, respectively, multiple sclerosis or amyotropic lateral sclerosis [R. L. Knobler, supra; M. A. Faerkkilae, supra].
Based on in-vitro studies, it has been reported that gamma interferon is less anti-virally active than alpha or beta interferon (see, for example, A. Munoz, L. Carrasco, FEMS Microbiol. Letters, 21, pp. 105-11 (1984). For this reason, gamma interferon, to date, has not been used for the systemic treatment of viral diseases.
Patients with tumors have, up to now, been treated only in phase I studies, so that no prediction as to therapeutic effectiveness of gamma interferon in these diseases is possible [S. Yamazaki, Jpn. J. Med. Sci. Biol., 37, pp. 209-23 (1984); S. A. Sherwin et al., "A Preliminary Phase I Trial Of Partially Purified Interferon-.gamma. In Patients With Cancer", J. Biol. Resp. Modif., 3, pp. 599-607 (1984); J. U. Guttermann et al., "Pharmocokinetic Study Of Partially Pure .gamma.-Interferon In Cancer", Cancer Res., 44, pp. 4164-71 (1984); N. Niederle et al., in H. Kirchner and H. Schellekens (Eds.), The Biology of the Interferon System 1984 (1985)].
To date therefore, conventional methods and therapeutic agents have not proved to be effective in the treatment of many diseases. Accordingly, the need exists for a process which avoids the disadvantages of these conventional methods and agents while providing effective treatment for those diseases.